The CREATE-ECLA Randomized Controlled TrialThe CREATE-ECLA Trial Group Investigators* See also pp 427 and 489.
Overcoming chemorestistance to 5-fluorouracil (5-FU) could offer a new treatment option for highly malignant colon cancer. In our study, differential microRNA expression profiling revealed that miR-214 is downregulated in 5-FU-resistant colon cancer cells compared to normal cells. In vitro, miR-214 could sensitize non-resistant colon cancer cells and 5-FU-resistant colon cancer cellsto 5-FU. Functionally, miR-214 inhibited cell clone formation and cell growth and enhanced 5-FU-inducing cell apoptosis and caspase-3 levels. MiR-214 targeted heat shock protein 27 (Hsp27), as confirmed via dual luciferase reporter assays and western blots. Hsp27 also sensitized HT-29 and LoVo to 5-FU by enhancing cell apoptosis. Overexpression of Hsp27 could block miR-214 with an effect on the sensitivity of colon cancer cells to 5-FU. In conclusion, miR-214 sensitizes colon cancer cells to 5-FU by targeting Hsp27, indicating a significant role for this miRNA in colon cancer chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s11658-019-0143-3) contains supplementary material, which is available to authorized users.
Slit homolog 2 (Slit2) is distributed in various tissues and participates in numerous cellular processes; however, the role of Slit2 in the regulation of angiogenesis remains controversial, since it has previously been reported to exert proangiogenic and antiangiogenic activities. The present study aimed to investigate the effects of Slit2 on vascular endothelial cell proliferation and migration in vitro, and to reveal the possible underlying signaling pathway. Aortic endothelial cells were isolated from Sprague Dawley rats and cultured. Cell proliferation assay, cell migration assay, immunocytochemistry and small interfering RNA transfection were subsequently performed. The results demonstrated that exogenous Slit2 administration markedly suppressed TNF-α-induced endothelial cell proliferation and migration in vitro. In addition, TNF-α application upregulated the protein expression levels of vascular endothelial growth factor (VEGF) and Notch in RAECs, whereas Slit2 administration downregulated VEGF and Notch expression in RAECs cultured in TNF-α conditioned medium. Further studies indicated that knockdown of VEGF suppressed the effects of TNF-α on the induction of RAEC proliferation and migration. VEGF knockdown-induced inhibition of RAEC proliferation and migration in TNF-α conditioned medium was also achieved without Slit2 administration. Furthermore, VEGF knockdown markedly decreased Notch1 and Notch2 expression. These results indicated that Slit2 suppresses TNF-α-induced vascular endothelial cell proliferation and migration in vitro by inhibiting the VEGF-Notch signaling pathway. Therefore, Slit2 may inhibit the proliferation and migration of endothelial cells during vascular development.
Endovascular aortic repair (EVAR) is often followed by aneurysm recurrence. Alginate oligosaccharide (AOS) has potential antitumor properties as a natural product while the related mechanisms remain unclear. Toll-like receptor (TLR) signaling is associated with inflammatory activity of aneurysm and may be affected by miR-29b. Thus, inhibitory function of AOS on aneurysms was explored by measuring the important molecules in TLR4 signaling. After EVAR, a total of 248 aortic aneurysm patients were recruited and randomly assigned into two groups: AOS group (AG, oral administration 10-mg AOS daily) and control group (CG, placebo daily). The size of residual aneurysms, aneurysm recurrence, and side effects were investigated. Aneurysm recurrence was determined by Kaplan–Meier analysis. After 2 years, eight and two patients died in the CG and AG, respectively. The sizes of residual aneurysms were significantly larger in the CG than in the AG (P<0.05). The incidence of aneurysm recurrence was also significantly higher in the CG than in the AG (P<0.05). AOS treatment reduced the levels of miR-29b, TLR4, mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappa B), interleukin 1 (IL-1) beta, and interleukin 6 (IL-6). Overexpression and silence of miR-29b increased and reduced the level of TLR4, phospho-p65 NF-kappa B, phospho-p38 MAPK, IL-1 beta, and IL-6. Spearman’s rank correlation analysis shows that the level of miR-29b is positively related to the levels of TLR4, NF-kappa B, IL-1 beta, and IL-6 (P<0.05). Thus, AOS represses aneurysm recurrence by indirectly affecting TLR signaling via miR-29b.
Abstract. 125 I) seed implantation has been widely used for the treatment of unresectable advanced tumors. However, the molecular mechanisms underlying the tumor-suppressive effects of 125 I irradiation have not been fully elucidated. The present study demonstrated that 125 I irradiation suppresses cell viability and inhibits cell invasiveness of gastric cancer KATO-III and MKN45 cells. Further mechanistic analysis suggested the involvement of microRNA (miR)-181c in the inhibitory effects induced by 125 I irradiation. Methylated DNA immunoprecipitation coupled with quantitative-polymerase chain reaction demonstrated that treatment with 125 I irradiation, at the dose of 4 Gy, induced promoter demethylation of the miR-181c gene in KATO-III and MKN45 cells. Following irradiation, the expression of miR-181c was significantly increased, which may be attributed to the demethylation caused by 125 I irradiation. In addition, upregulation of miR-181c by administration of miR-181c mimics decreased cell invasion, suggesting the role of miR-181c as a tumor suppressor. More importantly, the tumor-suppressive effects of 125 I irradiation were significantly compromised by the introduction of miR-181c inhibitors. Overall, these results reveal that 125 I irradiation inhibits invasiveness of gastric cancer cells by reactivating miR-181c at the epigenetic level, thereby providing important molecular evidence for the anticancer effects of 125 I irradiation.
BackgroundIodine interstitial brachytherapy has been widely reported for treating colorectal cancer (CRC). However, the inhibitory molecular mechanism of iodine-125 (I-125) on CRC has not been reported.MethodsTo illustrate the inhibitory mechanism of iodine-125 (I-125) on CRC, we established the animal models of CRC via the injection of HCT-8 cells into nude mice. Subsequently, the I-125 granules were implanted into the tumor of the animal model at different dosages. Proliferating cell nuclear antigen and terminal transferase dUTP nick end labeling were used to detect the apoptosis of the tumor cells. Immunohistochemistry SP staining was used to measure the expression of p53 protein. The protein levels were examined with western blot and ELISA. Meanwhile, microvessel density (MVD) was counted by endothelial cells immunostained by anti-CD34 antibody.ResultsThe results showed that I-125 protests against CRC via increasing the protein level of p53 and decreasing the level of vascular endothelial growth factor (VEGF), leading to the decrease of MVD in CRC (P <0.0001). An effective inhibition dosage of I-125 ranged from 0.4 to 0.8 mCi.ConclusionsThe inhibitory mechanisms of iodine on CRC acted through an increase in the level of p53 and a decrease in the level of VEGF, resulting in a decrease of MVD.
The VLP positive rate of the STEMI group is higher than that of the NSTEMI group.
In cardiac tissues, myoblast atrial myocytes continue to be exposed to mechanical forces including shear stress. However, little is known about the effects of shear stress on atrial myocytes, particularly on ion channel function, in association with disease. The present study demonstrated that the Ca2+-activated K+ channel (KCa)2.3 serves a vital role in regulating arterial tone. As increased intracellular Ca2+ levels and activation of histone acetyltransferase p300 (p300) are early responses to laminar shear stress (LSS) that result in the transcriptional activation of genes, the role of p300 and the phosphoinositide3-kinase (PI3K)/protein kinase B (Akt) pathway, an intracellular pathway that promotes the growth and proliferation rather than the differentiation of adult cells, in the LSS-dependent regulation of KCa2.3 in cardiac myoblasts was examined. In cultured H9c2 cells, exposure to LSS (15 dyn/cm2) for 12 h markedly increased KCa2.3 mRNA expression. Inhibiting PI3K attenuated the LSS-induced increases in the expression and channel activity of KCa2.3, and decreased the phosphorylation levels of p300. The upregulation of these channels was abolished by the inhibition of Akt through decreasing p300 phosphorylation. ChIP assays indicated that p300 was recruited to the promoter region of the KCa2.3 gene. Therefore, the PI3K/Akt/p300 axis serves a crucial role in the LSS-dependent induction of KCa2.3 expression, by regulating cardiac myoblast function and adaptation to hemodynamic changes. The key novel insights gained from the present study are: i) KCa2.3 was upregulated in patients with atrial fibrillation (AF) and in patients with AF combined with mitral value disease; ii) LSS induced a profound upregulation of KCa2.3 mRNA and protein expression in H9c2 cells; iii) PI3K activation was associated with LSS-induced upregulation of the KCa2.3 channel; iv) PI3K activation was mediated by PI3K/Akt-dependent Akt activation; and v) LSS induction of KCa2.3 involved the binding of p300 to transcription factors in the promoter region of the KCa2.3 gene.
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